Cardiovascular disease is the leading cause of morbidity and mortality in western countries. Advanced glycation end products (AGEs) are bioactive molecules implicated in the pathogenesis of atherosclerosis and cardiovascular disease. Major sources of systemic AGEs are endogenous AGEs generated in the body and exogenous AGEs found in foods. The western diet is rich in AGEs that are formed when food is processed at high temperatures. AGEs play a role in atherosclerosis by cross-linking collagen in vessel walls, increasing oxidation of low-density lipoprotein, and increasing inflammation through activation of the receptor for AGE (RAGE). Circulating isoforms of RAGE include endogenous secretory RAGE (esRAGE), a splice variant of RAGE that is secreted into blood and lacks the transmembrane and cytoplasmic portion of the receptor, and truncated forms of RAGE that have been cleaved from the cell surface. Based upon knowledge of the AGE-RAGE pathway and our preliminary data, we hypothesize that older people with elevated serum AGEs, sRAGE, and esRAGE are at greater risk of developing adverse cardiovascular outcomes, such as coronary heart disease, heart failure, stroke, and cardiovascular disease mortality. We propose to characterize the relationship between AGEs and circulating RAGE with cardiovascular outcomes in the NIH-supported Health, Aging and Body Composition (Health ABC) Study, a community-based prospective study of aging. Serum AGEs and circulating RAGE will be measured at enrollment and examined in relation to prevalent cardiovascular disease and to incident cardiovascular diseases that have been assessed over ten years of follow-up. Serum AGEs and circulating RAGE will also be examined in relation to aortic pulse wave velocity, abnormal glucose metabolism, and markers of inflammation. The proposed study will determine whether or not serum AGEs are a major risk factor for cardiovascular disease and will provide insight into the biological mechanisms by which serum AGEs and their circulating receptors may be involved in the pathogenesis of cardiovascular disease. AGEs are a potentially modifiable risk factor, as circulating AGEs can be lowered by dietary modification and by pharmacological intervention with AGE inhibitors or AGE-breakers. PUBLIC HEALTH RELEVANCE: This project is relevant to public health as it aims to characterize the relationship between advanced glycation end products, bioactive compounds found in high amounts in the western diet, and cardiovascular disease in older adults.